1-Benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (Donepezil) of formula 1, is a new drug used in the treatment of mild to moderate cases of SDAT (Senile Dementia of Alzheimers Type).

There are many processes as disclosed in the prior arts for producing donepezil of formula 1. U.S. Pat. No. 4,895,841 wherein substituted 1-indanone-2-phosphonate prepared from 2-bromo-5,6-dimethoxyindanone and triethyl phosphite, is treated with 1-benzylpiperidine-4-carboxaldehyde in the presence of a strong base, such as lithium diisopropylamide (LDA), followed by catalytic reduction using palladium on carbon in tetrahydrofuran (40 volumes) to yield donepezil with an overall yield of 50.8%. This process however suffers with few limitations i.e. it employs triphenylphosphonium methoxymethyl chloride, which is expensive and toxic and the overall yield of this process is quite low. (scheme 1).

U.S. Pat. No. 5,606,064 describes another route to prepare donepezil via the reduction of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-ylidene)methyl]pyridinium salt in presence of platinum dioxide as catalyst and methanol as solvent with a yield of 58.5% (scheme 2). However, the reduction of an olefinic bond and a pyridinium ring in presence of a benzyl group, as described in the process is difficult to achieve and leads to unwanted side products mainly debenzylated product and the reaction time for completion is also too long which is 24 hrs.

U.S. Pat. No. 6,252,081 discloses a process, which involves the selective reduction of pyridinium ring of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]pyridinium salt using platinum oxide as catalyst and methanol (15 volumes) as a solvent. This process also leads to the formation of impurities, which are difficult to separate and affects the overall reaction yield along with the purity of the compound (Scheme 3).

U.S. Pat. No. 6,649,765 and US Patent Application No. 20040158070 describe the synthesis of donepezil by the reduction of 4-[(5,6-dimethoxy-1-indanon-2-ylidene)methyl]pyridine using noble metal oxide or non-oxide noble metal catalyst in a mixture of solvents such as acetic acid and methanol (30-40 volumes) at 25-50 psi gauge followed by benzylation (Scheme 4).

US Patent Application No. 20040143121 discloses the process for the preparation of donepezil which involves the reduction of compound 4-[(5,6-dimethoxy-1-indanon-2-ylidene)methyl]pyridine using platinum dioxide or Pd/C as catalyst, and in a mixture of solvents such as acetic acid and methanol (15-20 volumes), whereas WO 2004082685 describes the preparation of donepezil which comprises the two step reduction starting from 4-[(5,6-dimethoxy-1-indanon-2-ylidene)methyl]pyridine via the preparation of intermediate 4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]pyridine using mixture of methanol and methylene chloride as a solvent (20-25 volumes).
The processes disclosed in the prior art have several limitations like multiple chemical steps, overall low yields, side product formation, use of expensive or hazardous reagents. Furthermore, the most common drawback is the use of very large, usually 15-40 volume of solvent as well as large amount of noble metal catalyst usually 10% in the hydrogenation step. The use of such large volume of solvent in the hydrogenation step is a major safety risk. Moreover, it creates not only handling problem but subsequently large volume of solvents has to be distilled off to isolate the hydrogenated product. Thus the productivity of the hydrogenation reactor is severely curtailed and it becomes a bottleneck in the large-scale production of donepezil. The reason for the use of large volume of solvent could be the poor solubility of the pre-hydrogenation intermediates. Therefore, there is a need to develop novel pre-hydrogenation intermediates, which would be easily soluble in the solvents commonly used in the hydrogenation step to make the large-scale production of donepezil safe and yet economically feasible.
Present invention bridges this gap and discloses a novel process, which eliminates the excessive use of solvent in the hydrogenation step and is suitable for industrial scale up.